Demyelination shunts depolarizing current out of the nerve. As a result, nerve conduction of action potentials can be slowed or even eliminated. The later is known as conduction block. This change causes neurological disabilities such as sensory loss, vision loss, and limb paralysis in a variety of neurological diseases. We have found that patients and mice with FIG4 deficiency develop a demyelinating neuropathy. This demyelination closely recapitulates features in acquired demyelinating diseases. The FIG4-deficient cells exhibit lysosomal membrane fission defect with an abnormally suppressed efflux of intralysosomal Ca2+ through a lysosomal Ca2+ channel. These observations lead us to propose the hypothesis below. Hypothesis: FIG4 deficiency deactivates Ca2+-channels on lysosomal membranes and prevents Ca2+ release from lysosomes. This, in turn, impairs lysosomal membrane trafficking (lysosomal fission defect), leading to segmental demyelination. Toward this end, we propose the following specific aims. Specific Aim 1. To test the hypothesis that FIG4 deficiency suppresses lysosomal fission by blocking the efflux of intralysosomal Ca2+ in myelinating Schwann cells. Specific Aim 2. To determine whether FIG4-deficiency in Schwann cell sensitizes the cell to demyelination. In this aim, we will utilize Fig4 conditional knockout mice to examine how the impaired lysosomal Ca2+-homeostasis in Fig4-/- Schwann cells may sensitize the cells to demyelination. Specific Aim 3. To test the hypothesis that FIG4 in myelinating Schwann cells is required for remyelination. Significance of lysosomal membrane trafficking in de/remyelination is essentially unexplored. Our results have demonstrated a novel signaling pathway in FIG4 deficiency that appears to be critical in lysosomal membrane trafficking and demyelination. Since demyelination in Fig4-/- nerves recapitulates key features of acquired demyelinating diseases, results from this project are also relevant to other acquired demyelinating disorders. Furthermore, our preliminary results suggest a high probability in developing therapeutic interventions for demyelination in FIG4 deficiency.